CanRisk

At present, NHS-funded constitutional (germline) genomic testing is offered if the likelihood of identifying a causative constitutional pathogenic variant in the patient is at least 10%. A number of models have been developed to try to predict the likelihood of identifying an underlying pathogenic variant in BRCA1, BRCA2 or other breast or ovarian cancer susceptibility genes in an individual with a personal and/or family history of cancer – of which BOADICEA, the model that underpins the CanRisk tool – is one. CanRisk incorporates a range of personal and clinical risk factors to provide individualised estimates of future breast and/or ovarian cancer risk. It is designed for use by healthcare professionals.

BOADICEA (the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) is a risk prediction model that can be used to estimate a patient’s future risk of breast and ovarian cancer, as well as to estimate risk of an underlying constitutional (germline) pathogenic variant in the breast and/or ovarian cancer predisposition genes BRCA1, BRCA2, PALB2, CHEK2, ATM, BARD1, RAD51D, RAD51C and BRIP1.

CanRisk is the web interface for BOADICEA, supported by grant PPRPGM-Nov20\100002 from Cancer Research UK. Risks are presented in graphical as well as textual formats to help users communicate them to patients. It is designed for use by healthcare professionals to support conversations with patients and to facilitate communication of risk, rather than for direct use by patients.

Risk factors included in the breast and ovarian cancer risk estimates are listed below, and include genetic factors (high-risk constitutional (germline) variants and polygenic risk scores), personal and family history, lifestyle and reproductive factors.

Table 1: Risk factors included in CanRisk estimates

Genotypic information included in the model

Cancer risks estimated by CanRisk are based on those associated with heterozygous pathogenic truncating variants. Caution should be used when estimating cancer risks in individuals who carry pathogenic missense variants in relevant genes of interest. Similarly, caution is required when estimating cancer risk in individuals who carry biallelic variants in CHEK2 or ATM, as risks in those individuals are known to be higher than those in heterozygotes.

Family history information included in the model

CanRisk considers cancer history information in individuals with a valid year of birth and age (or age at death). Without these details, only the individual’s genomic test results will be considered in their risk estimate. If year of birth and age are unavailable, it is recommended that a reasonable estimate be included to avoid underestimating the impact of family cancer history.

Only invasive epithelial ovarian cancers should be included in the CanRisk model. Non-epithelial cancers (such as germ cell tumours or tumours associated with low malignant potential) are not typically associated with constitutional (germline) pathogenic variants in the genes included in the model, and should not be considered. Primary cancers of the fallopian tube and peritoneum can be included, but other gynaecological cancers (such as endometrial and cervical) should not be included. Similarly, only invasive breast cancers, and not cancers in situ, should be included.

Cancer risks cannot be calculated by CanRisk for men, for patients older than 80 years of age or for women with more than one primary breast cancer, although the tool can still be used to calculate the likelihood of identifying a pathogenic constitutional (germline) variant in the genes included in the model in these individuals.

As per the current National Genomic Test Directory, testing can be offered to:

• individuals affected by breast, ovarian, pancreatic or prostate cancer with an estimated likelihood of identifying a causal constitutional (germline) pathogenic variant of least 10%, as calculated by CanRisk.

Registration for a CanRisk account is open to any medical practitioner or academic researcher with appropriate professional indemnity. Instructions for using the resource are available in the Quick Start Guide. A patient-facing resource (MyCanRisk) is under development.

A recent national meeting was convened by the UK Cancer Genetics Group and Cancer Research UK-funded CanGene-CanVar, a programme with the aim of standardising the use of CanRisk to determine eligibility for constitutional (germline) genomic testing and to determine cancer risk management. The use of CanRisk is endorsed by these organisations, but further clarity regarding minimum acceptable dataset, and whether CanRisk can be used to determine category of breast cancer risk, is awaited.

• CanRisk is the web interface for BOADICEA, a risk prediction model that can be used to estimate a patient’s future risk of breast and ovarian cancer, as well as to estimate risk of an underlying constitutional (germline) pathogenic variant in numerous breast and/or ovarian cancer predisposition genes.
• Risk factors included in the CanRisk estimates include genetic factors, personal and family history, lifestyle and reproductive factors.
• Cancer risks cannot be calculated by CanRisk for men, for patients older than 80 years of age or for women with more than one primary breast cancer.

For clinicians

• CanRisk: Quick Start Guide
• NICE: Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer
• UK Cancer Genetics Group (UKCGG): UKCGG consensus meetings

References:

• Carver T, Hartley S, Lee A and others. ‘CanRisk tool: A web interface for the prediction of breast and ovarian cancer risk and the likelihood of carrying genetic pathogenic variants‘. Cancer Epidemiology, Biomarkers & Prevention 2021: volume 30, issue 3, pages 469–473. DOI: 10.1158/1055-9965.EPI-20-1319
• Lee A, Mavaddat N, Wilcox AN and others. ‘BOADICEA: A comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors‘. Genetic in Medicine 2019: volume 21, issue 8, pages 1,708–1,718. DOI: 10.1038/s41436-018-0406-9